SUMMARY Koch, Lauren Gerard Exercise capacity is a strong predictor of freedom from relative risk of dementia and cognitive impairment in humans [1]. A recent addition to this link is the influence of the more than 1000 different species of microorganisms living in the gut (microbiota) that can, in theory, either degrade or sustain cognitive health and either resist or promote onset of dementia [2, 3]. The goal of this supplement is to assess the link between exercise capacity, and cognitive health with changes in gut and serum microbiota in aging low capacity runner (LCR) and high capacity runner (HCR) exercise rat models. These selectively bred, genetically heterogeneous rat models segregate for numerous AD-comorbidities including metabolic syndrome, cardiovascular disease, stroke, hypertension, type 2 diabetes, fatty liver disease, and premature death [4]. We know from published work and preliminary data that LCR rats have evidence for Alzheimer-like neurodegeneration, cognitive impairments, mitochondrial dysfunction, chronic inflammation (e.g. elevated neutrophils and NETS), and substantial microbiota alterations. This suggests the hypothesis that by the process of the selection on LCR- HCR, the co-occurrence of the host genome and microbiome are important symbiotic factors for uncovering risks and prevention of AD. As an initial test of this theory, we will Aim 1. Track exercise capacity and cognitive function along with microbiota perturbations during aging. We will conduct a 1-year aging study in male and female LCR HCR rats starting at 16, 20 & 24 mo. of age (late-adult) to inform our understanding of the association between microbiome and differences in cognitive function with aging. Treadmill running capacity, VO2max, energy expenditure, peripheral immune markers, and cognitive function (e.g. Barnes Maze Test) will be tested. Blood and fecal samples will be collected for immune activity and microbiota testing. For example, immune profiles will inform us whether LCR and HCR bred rat models segregate for high neutrophil-to- lymphocyte ratio, a biomarker that is used to define AD humans. Increases in gut permeability (i.e., ?leaky gut?) may be a primary contributor to increases in age-related inflammation via release of intestinal contents into the circulation (i.e. serum microbiome). Aim 2. Establish evidence for the symbiotic relationship between host genome and microbiome for AD risk. We will perform 16S RNA sequencing of fecal and serum samples. We will use a correlation analysis of relative abundance of bacterial and multiple traits to find significant associations between microbiota and AD risk phenotypes. This administrative supplement will fortify the major objective of the Exercise Rat Research Resource to explore the mechanistic basis of complex diseases. This activity will strengthen All Specific Aims of the parent grant by: 1) adding evaluation of cognitive function along with exercise testing (Aim 1), 2) profiling of new clinical markers (immune panel) and bioanalytes (fecal pellets, microbiota and gut tissues) as a common reference of the health status of the LCR-HCR models (Aim 2), and 3) attracting new users who can use the rat resource to resolve causation of disease risks at the mechanistic level (Aim 3).